Our Alzheimer's Disease Research Center (ADRC) has a major commitment to investigations of aging and age-associated diseases, including illnesses that occur in subjects with Alzheimer's disease (AD) and in older individuals with Down's Syndrome (DS). We believe that genetic factors, abnormalities of protein processing, and age play important roles in the cognitive/memory impairments and in the brain pathology that occur in these individuals. The interface between biological processes and clinical issues (i.e., subtypes of disease, risk and prognostic factors, and relationship of clinical phenotype to brain pathology) are addressed in Cores B and C. At a basic science level, we need more information about the mechanisms that lead to: selective vulnerability of specific neurons; cytoskeletal abnormalities in these cells; the formation of senile plaques; the pathways by which disease spreads; and the occurrence of death of neurons. Moreover, no therapies are available for these disorders. Building upon Core support, Projects 1-6 address some of these issues, focusing on clinical-pathological correlations (Project 2,3,5), the problems of selective vulnerability and the spatial/temporal evolution of pathology (Projects 1,3,4), and molecular mechanisms that lead to neuronal abnormalities characteristic of aging (Projects 1,2), AD (Projects 1,4,5), and DS (Projects 1,3). We believe that these disorders may eventually be amenable to therapeutic approaches, and, in Project 6, we test three biological therapies (i.e., nerve growth factor, peripheral nerve grafts, and neural grafts) designed to influence basal forebrain cholinergic neurons in several animal models. Ultimately, these lines of research should provide new insights into the natural history of the disease, predictors of prognosis, mechanisms of cellular pathology, and, possibly, new approaches to treatment. Finally, our ADRC is committed to the training of young physicians/scientists who represent our best hope for eventually being able to deal with age-associated disorders, such as AD.